Ectopic Granule Cells in the Dentate Gyrus

描述(申请人提供)：已提出成年齿状回颗粒细胞(GC)的出生后神经发生与认知和情绪调节有关的重要功能，许多疾病可能会出现出生后神经发生障碍。与大多数关于成人神经发生的研究不同，大多数研究集中在GC所在的正常区域-颗粒细胞层，在这一建议中，我们建议一个不同的区域是重要的，邻近的肺门。我们认为，在各种病理条件下，成年出生的GCs错误地迁移到肺门，这些异位GCs(EGCs)导致功能障碍。这一假说是基于对癫痫动物模型中的EGCs的研究，在该动物模型中，发现肺门EGCs发育，并表现出异常的兴奋性和回路。令人惊讶的是，我们现在已经在阿尔茨海默病(AD)等精神疾病的动物模型中发现了肺门EGCs的证据。与此同时，其他实验室也报告称，精神分裂症和酒精中毒会导致成年出生的GC迁移不当。在我们对模拟AD的转基因小鼠进行的初步研究中，EGCs似乎发展出异常的兴奋性和电路，因此我们假设它们将像在癫痫动物模型中所做的那样扰乱电路功能。我们也有初步数据表明，精神疾病患者的尸检标本中存在EGCs。因此，在这项提案中，我们将试图证明肺门EGCs不仅与癫痫有关，而且与精神疾病有关。我们假设GCs在精神障碍中发展，因为导致这些疾病的分子机制也破坏了控制GCs迁移的正常信号。提出的实验将使用1)解剖学方法证明EGCs存在于精神疾病的动物模型中，2)切片电生理学证明EGCs在这些动物模型中具有异常的兴奋性和回路，3)行为学实验证明EGCs在体内伴随着功能障碍，以及4)计算模型显示EGCs将在正常齿状回网络的计算模型中扰乱齿状回的特定功能。这一结果意义重大，因为它们将为影响认知和行为的许多疾病的共同病理提供证据：齿状回门部的EGCs。这一见解可能会导致针对迁移分子机制的新疗法的开发。EGCs成像可能成为一种新的诊断策略。改进的治疗和诊断都很重要，因为许多精神疾病是复杂的，在诊断和治疗方面都存在困难。 公共卫生相关性：通常认为，出生后齿状回的神经发生可以改善认知功能和情绪，因此增加神经发生的比率是有益的。然而，我们认为，当存在病理条件时，这种积极的影响可能不会发生，因为这些条件扰乱了控制正常迁移的线索。因此，异位神经元可以发育和破坏功能，支持正常迁移的治疗策略将防止功能障碍。

DESCRIPTION (provided by applicant): It has been suggested that postnatal neurogenesis of granule cells (GCs) in the adult dentate gyrus serves important functions related to cognition and mood regulation, and that impairments in postnatal neurogenesis may occur in many diseases. In contrast to most research about adult neurogenesis, which focuses on the normal area where GCs are located, the granule cell layer, in this proposal we suggest a different area is important, the adjacent hilus. We propose that, in a variety of pathological conditions, adult-born GCs mismigrate into the hilus, and these ectopic GCs (EGCs) cause dysfunction. This hypothesis is based on studies of EGCs in an animal model of epilepsy, where it was found that hilar EGCs develop, and display abnormal excitability and circuitry. Surprisingly, we have now found evidence for hilar EGCs in animal models of psychiatric illness, such as Alzheimer's disease (AD). In parallel, other laboratories have reported that mismigration of adult-born GCs occurs in schizophrenia and alcoholism. In our pilot studies from transgenic mice that simulate AD, EGCs appear to develop abnormal excitability and circuitry, so we hypothesize that they will disrupt circuit function like they do in animal models of epilepsy. We also have preliminary data suggesting that EGCs are present in postmortem specimens from patients with psychiatric illness. Therefore, in this proposal we will attempt to show that hilar EGCs are not only relevant to epilepsy, but psychiatric disease. We hypothesize that EGCs develop in psychiatric disorders because the molecular mechanisms that are responsible for these conditions also disrupt the normal cues that control migration of GCs. The experiments that are proposed will use 1) anatomical approaches to prove that EGCs exist in animal models of psychiatric diseases, 2) slice electrophysiology to prove the EGCs have abnormal excitability and circuitry in these animal models, 3) behavioral experiments to prove the EGCs are accompanied by dysfunction in vivo, and 4) computational modeling to show that EGCs will disrupt specific functions of the dentate gyrus in a computational model of the normal dentate gyrus network. The results would be significant because they would provide evidence for a common pathology across many diseases that affect cognition and behavior: EGCs in the hilus of the dentate gyrus. This insight could lead to the development of new therapeutics to target the molecular mechanisms of migration. Imaging EGCs could become a new diagnostic strategy. Improved therapeutics and diagnostics are both important because many psychiatric disorders are complex, presenting difficulties both in diagnosis as well as treatment. PUBLIC HEALTH RELEVANCE: It is often assumed that postnatal neurogenesis in the dentate gyrus improves cognitive function and mood, so increasing the rate of neurogenesis is beneficial. However, we suggest that this positive effect may not occur when pathological conditions exist, because these conditions disrupt the cues that control normal migration. Therefore, ectopic neurons can develop and disrupt function, and therapeutic strategies that support normal migration would prevent dysfunction.